Kvello Anne Marte Sjursen, Andersen Jannike Mørch, Øiestad Elisabeth Leere, Mørland Jørg, Bogen Inger Lise
Department of Drug Abuse Research, Domain for Forensic Sciences, Norwegian Institute of Public Health (A.M.S.K., J.M.A., E.L.Ø., J.M. and I.L.B.) and School of Pharmacy, University of Oslo (E.L.Ø.) Oslo, Norway
Department of Drug Abuse Research, Domain for Forensic Sciences, Norwegian Institute of Public Health (A.M.S.K., J.M.A., E.L.Ø., J.M. and I.L.B.) and School of Pharmacy, University of Oslo (E.L.Ø.) Oslo, Norway.
J Pharmacol Exp Ther. 2016 Aug;358(2):181-9. doi: 10.1124/jpet.116.233510. Epub 2016 May 23.
Immunotherapy can provide a supplemental treatment strategy against heroin use on the principle of sequestering the active drug in the bloodstream, thereby reducing its distribution to the brain. Previous studies have shown that heroin's first metabolite, 6-monoacetylmorphine (6-MAM), is the main mediator of acute heroin effects. The objective of the present study was to characterize the pharmacological potential of a monoclonal antibody against 6-MAM (anti-6-MAM mAb) to counteract the heroin response. The individual contributions from heroin and 6-MAM to heroin effects were also examined by pretreating mice with anti-6-MAM mAb (10-100 mg/kg) prior to either heroin or 6-MAM injection (1.25-2.5 μmol/kg). The opioid-induced behavioral response was assessed in a locomotor activity test, followed by opioid and antibody quantification in blood and brain tissue. Pretreatment with mAb caused a profound reduction of heroin- and 6-MAM-induced behavior, accompanied by correspondingly decreased levels of 6-MAM in brain tissue. mAb pretreatment was more efficient against 6-MAM injection than against heroin, leading to an almost complete blockade of 6-MAM-induced effects. mAb pretreatment was unable to block the immediate (5-minute) transport of active metabolites across the blood-brain barrier after heroin injection, indicating that heroin itself appears to enhance the immediate delivery of 6-MAM to the brain. The current study provides additional evidence that 6-MAM sequestration is crucial for counteracting the acute heroin response, and demonstrates the pharmacological potential of immunotherapy against heroin use.
免疫疗法可以基于将活性药物隔离在血液中，从而减少其向大脑分布的原理，提供一种针对海洛因使用的补充治疗策略。先前的研究表明，海洛因的第一种代谢产物6-单乙酰吗啡（6-MAM）是海洛因急性效应的主要介导物。本研究的目的是表征一种针对6-MAM的单克隆抗体（抗6-MAM单克隆抗体）对抗海洛因反应的药理学潜力。还通过在注射海洛因或6-MAM（1.25-2.5 μmol/kg）之前用抗6-MAM单克隆抗体（10-100 mg/kg）预处理小鼠，来研究海洛因和6-MAM对海洛因效应的个体贡献。在运动活动测试中评估阿片类药物诱导的行为反应，随后对血液和脑组织中的阿片类药物和抗体进行定量。用单克隆抗体预处理可显著降低海洛因和6-MAM诱导的行为，同时脑组织中6-MAM的水平相应降低。单克隆抗体预处理对6-MAM注射的效果比对海洛因更有效，导致6-MAM诱导的效应几乎完全被阻断。单克隆抗体预处理无法阻断海洛因注射后活性代谢产物在5分钟内穿过血脑屏障的转运，这表明海洛因本身似乎会增强6-MAM向大脑的即时递送。当前的研究提供了额外的证据，表明隔离6-MAM对于对抗海洛因急性反应至关重要，并证明了免疫疗法针对海洛因使用的药理学潜力。
